Tumor necrosis factor (TNF) superfamily receptor IgM antibodies and uses thereof

Abstract

This disclosure provides dimeric, pentameric, and hexameric Tumor Necrosis Factor (TNF) superfamily receptor protein binding molecules and methods of using such binding molecules to direct apoptosis-mediated killing of TNF receptor-expressing cells.

What is claimed is: 
     
       1. An isolated IgM antibody comprising five or six identical bivalent binding units,
 wherein each binding unit comprises two IgM heavy chain constant regions, each associated with an identical antigen-binding domain, 
 wherein the IgM heavy chain constant regions each comprise a Cμ1 domain, a Cμ2 domain, a Cμ3 domain, and a Cμ4-tp domain, 
 wherein the antigen-binding domains of the antibody specifically and agonistically bind to a tumor necrosis factor (TNF) superfamily receptor protein, 
 wherein the antibody can cross-link at least three identical TNF superfamily receptor proteins expressed on the surface of a cell, thereby activating signal transduction in the cell; and 
 wherein the antibody can activate TNF superfamily receptor-mediated signal transduction in a TNF receptor superfamily-expressing cell at a higher potency than an equivalent amount of a bivalent IgG antibody or fragment thereof comprising two of the same antigen binding domains, which also specifically binds to and agonizes the same TNF superfamily receptor protein. 
 
     
     
       2. The antibody of  claim 1 , wherein the activation of signal transduction can trigger apoptosis, proliferation and/or morphogenesis in the cell in which the receptor protein is expressed. 
     
     
       3. The antibody of  claim 2 , wherein the signal transduction can trigger apoptosis, and wherein the TNF superfamily receptor protein is TNFR1 (DR1), TNFR2, TNFR1/2, CD40 (p50), Fas (CD95, Apo1, DR2), CD30, 4-1BB (CD137, ILA), TRAILR1 (DR4, Apo2), TRAILR2 (DR5), TRAILR3 (DcR1), TRAILR4 (DcR2), OPG (OCIF), TWEAKR (FN14), LIGHTR (HVEM), DcR3, DR3, EDAR, or XEDAR. 
     
     
       4. The antibody of  claim 2 , wherein the signal transduction can trigger proliferation, and wherein the TNF superfamily receptor protein is TNFR1/2, GITR (AITR), TACI, BCMA, TWEAKR (FN14), RANK (TRANCER), CD27, CD40 (p50), OX40 (CD134), LT-βR, TNFR1 (DR1), or TNFR2. 
     
     
       5. The antibody of  claim 2 , wherein the signal transduction can trigger morphogenesis, and wherein the TNF superfamily receptor protein is Fas (CD95, Apo1, DR2), TRAILR1 (DR4, Apo2), DR5 (TRAILR2), TRAILR3 (DcR1), TRAILR4 (DcR2), OPG (OCIF), CD40 (p50), EDAR, XEDAR, or TNFR1/2. 
     
     
       6. The antibody of  claim 1 , wherein the five or six binding units are human, humanized, or chimeric IgM binding units. 
     
     
       7. The antibody of  claim 1 , wherein the cell is a cancer cell. 
     
     
       8. The antibody of  claim 1 , which is pentameric, and further comprises a J chain, or fragment thereof, or variant thereof. 
     
     
       9. The antibody of  claim 1 , wherein the IgM heavy chain constant regions are human IgM constant regions. 
     
     
       10. The antibody of  claim 1 , wherein each binding unit comprises two IgM heavy chains each comprising a VH situated amino terminal to the IgM constant region or fragment thereof, and two immunoglobulin light chains each comprising a VL situated amino terminal to an immunoglobulin light chain constant region. 
     
     
       11. A composition comprising the antibody  claim 1 . 
     
     
       12. The antibody of  claim 2 , which can trigger apoptosis, morphogenesis, or proliferation of a TNF superfamily receptor protein-expressing cell at higher potency than an equivalent amount of a monospecific, bivalent IgG1 antibody or fragment thereof comprising two of the same antigen binding domains that specifically binds to the same TNF superfamily receptor protein epitope as the TNF superfamily receptor protein binding domain. 
     
     
       13. A method of inducing TNF superfamily receptor-mediated signal transduction in a TNF superfamily receptor-expressing cell, which comprises contacting the TNF superfamily receptor-expressing cell with the antibody of  claim 1 . 
     
     
       14. The method of  claim 13 , wherein the antibody triggers apoptosis, morphogenesis, or proliferation of the TNF superfamily receptor protein-expressing cell at higher potency than an equivalent amount of a monospecific, bivalent IgG1 antibody or fragment thereof that specifically binds to the same TNF superfamily receptor protein. 
     
     
       15. A method of treating cancer comprising administering to a subject in need of treatment an effective amount of the antibody of  claim 1 . 
     
     
       16. The method of  claim 15 , wherein the subject is human.